Recent studies have highlighted the importance of Patient-Oriented Research, drawing attention to the relatively small number of investigators trained to conduct high-quality clinical research. Appropriate and committed mentoring is critical for attracting talented individuals to clinical investigation and providing them with quality training and career guidance at three specific points: 1) at the premedical and medical school level; 2) during specialty and subspecialty training; and 3) during the transition from Fellow to independent investigator. Mechanisms have been established within the applicant's Unit and Institution, within the Partner's Healthcare System and Harvard Medical School to recruit and provide the environment for training of such individuals. However, the success of each of these initiatives is critically dependent on the availability of qualified investigators who can teach by example and are committed and able to invest in mentoring the next generation. There is a particular need for rigorous and innovative patient-oriented investigation in the areas of reproductive health in women, This grant provides the mechanism for supporting the mentoring activities of the applicant while ensuring that her own patient-oriented research efforts are not compromised. An important area of the Pl's research is focused on the complex interrelationships between FSH, estradiol and the inhibins. While both estradiol and the inhibins appear to contribute to the negative feedback control of FSH in women, their relative roles in the precise control of FSH during the follicular and luteal phases of the normal menstrual cycle have not been delineated. Coordinated secretion of estradiol and the inhibins is altered in reproductive aging (estradiol increased in the presence of low inhibin) and African-American women (increased estradiol relative to Caucasian women with identical inhibin levels). Determining the mechanisms responsible for these changes will provide us with important insights into the interactions of inhibin, estradiol and gonadotropins in normal reproductive physiology. A complementary area of research involves the neuroendocrine mechanisms that contribute to aging of the female reproductive system in the human. The underlying hypothesis is that there are changes in the physiology of hypothalamic gonadotropin-releasing hormone (GnRH) secretion and pituitary responsiveness in women that are specifically related to aging. This proposal will study the age-related changes in pituitary function in postmenopausal women (using both clinical approaches and autopsy studies) and the age-related changes in gonadal steroid feedback on the hypothalamic-pituitary axis, investigating both negative and positive feedback and using PET scanning to address the sites of action of estrogen action in the brain. The information derived from these studies will provide basic insights into the effects of aging on the brain in women and may also have important implications for our understanding of the potential neuroendocrine contributions to reproductive aging and menopause. Taken together, these projects provide a strong program for training in clinical investigation that utilizes a variety of methodologies to address critical hypotheses in reproductive biology.
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